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Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenic
Open accessAbstract
Mucus-invasive bacterial biofilms are identified on the colon mucosa of approximately 50% of colorectal cancer (CRC) patients and approximately 13% of healthy subjects. Here, we test the hypothesis that human colon biofilms comprise microbial communities that are carcinogenic in CRC mouse models. Homogenates of human biofilm-positive colon mucosa were prepared from tumor patients (tumor and paired normal tissues from surgical resections) or biofilm-positive biopsies from healthy individuals undergoing screening colonoscopy; homogenates of biofilm-negative colon biopsies from healthy individuals undergoing screening colonoscopy served as controls. After 12 weeks, biofilm-positive, but not biofilm-negative, human colon mucosal homogenates induced colon tumor formation in 3 mouse colon tumor models (germ-free ApcMinΔ850/+;Il10-/- or ApcMinΔ850/+ and specific pathogen-free ApcMinΔ716/+ mice). Remarkably, biofilm-positive communities from healthy colonoscopy biopsies induced colon inflammation and tumors similarly to biofilm-positive tumor tissues. By 1 week, biofilm-positive human tumor homogenates, but not healthy biopsies, displayed consistent bacterial mucus invasion and biofilm formation in mouse colons. 16S rRNA gene sequencing and RNA-Seq analyses identified compositional and functional microbiota differences between mice colonized with biofilm-positive and biofilm-negative communities. These results suggest human colon mucosal biofilms, whether from tumor hosts or healthy individuals undergoing screening colonoscopy, are carcinogenic in murine models of CRC.
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“The enrichment of bacterial species from the oral cavity is characteristic of the CRC GOMS50,76–79, along with an enrichment in invasive polymicrobial bacterial biofilms in patients with right-sided tumours76,80,81.”
From Gut OncoMicrobiome Signatures (GOMS) as next-generation biomarkers for cancer immunotherapy (2023) · cites this paper as [80]
Experimental — accuracy not yet measuredIn the citing paper
“It is now well appreciated that gut microbiota affect anticancer immunity, controlling spontaneous tumor growth (Arthur et al., 2012; Dejea et al., 2018; Tomkovich et al., 2019) as well as response to chemo- and immunotherapy (Iida et al., 2013; Mager et al., 2020; Paulos et al., 2007; Sivan et al., 2015; Tanoue et al., 2019; Vetizou et al., 2015; Viaud et al., 2013).”
From Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment (2021) · cites this paper as Tomkovich et al., 2019
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“Several studies show that CRC tissues are enriched for polymicrobial biofilms, particularly on proximal colon tumors.(8,10,11) This observation correlates with our CPRD cohort findings in which antibiotic exposure was associated with increased risk of proximal/right colon cancer.”
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“Importantly, some of the most compelling evidence demonstrates that colonic biofilms can cause colorectal cancer in mice [56].”
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“Additional FISH analysis was conducted on biofilm-positive tumor tissues with probes to detect Bacteroidetes , Lachnospiraceae , Fusobacteria , and Proteobacteria (12, 13).”
InfluentialSelf-citationBacteriophage-mediated manipulations of microbiota in gastrointestinal diseases
Haddad, L. E., Mendoza, J. F., & Jobin, C. (2022) · Frontiers in Microbiology · doi:10.3389/fmicb.2022.1055427 · Cited by 43
“Since bacterial biofilm formation is associated with CRC and could promote tumorigenesis in preclinical models (Dejea et al., 2014; Tomkovich et al., 2019), these findings may have chemo-preventive implication.”
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Fluoroquinolones and Biofilm: A Narrative Review
Geremia, N., Giovagnorio, F., Colpani, A., VITO, A. D., Botan, A., Stroffolini, G., Țoc, D. A., Zerbato, V., Principe, L., Madeddu, G., et al. (2024) · Pharmaceuticals · doi:10.3390/ph17121673 · Cited by 36
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“Invasive polymicrobial bio fi lms, composed of Fuso-bacterium spp., Lachnospiraceae , Bacteroidetes, and Proteobacteria exhibit pro-cancerogenic potential by activating epithelial signaling pathways relevant to tumorigenesis 113 – 115 .”
In sickness and health: Effects of gut microbial metabolites on human physiology
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“Although the gut microbiome is typically described as being composed of nonharmful or beneficial microorganisms, it is now appreciated that both individual species [8] or multiple community members acting together [9, 10] can exert pathogenic effects, which are often more subtle than those of classical pathogens.”
BackgroundThe effects of biofilms on tumor progression in a 3D cancer-biofilm microfluidic model
Deng, Y., Liu, S. Y., Chua, S. L., & Khoo, B. L. (2021) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2021.113113 · Cited by 36
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“have previously reported the presence of mucus-invasive biofilms on the colon mucosa of about half CRC samples and in only 13% of control specimens [23].”
BackgroundIntestinal biofilms: pathophysiological relevance, host defense, and therapeutic opportunities
Jandl, B., Dighe, S. N., Gasché, C., Makristathis, A., & Muttenthaler, M. (2024) · Clinical Microbiology Reviews · doi:10.1128/cmr.00133-23 · Cited by 36
“Pronounced polymicrobial biofilms have a high prevalence in patients with colorectal cancer (64, 130, 165), and mucus-invasive bacterial biofilms on the colon mucosa are observed in ~50% of cases compared to ~13% of healthy controls (143, 166).”
InfluentialLin, H., Wang, Q., Liu, L., Chen, Z., Das, R., Zhao, Y., Mao, D., & Luo, Y. (2020) · Frontiers in Microbiology · doi:10.3389/fmicb.2020.01256 · Cited by 32
“The association of biofilm formation with the virulence of pathogens has been confirmed to be correlated with inflammation, including a decrease in E-cadherin levels, an increase in IL-6 levels and activation of the STAT3 pathway (Tomkovich et al., 2019).”
BackgroundGut fungal mycobiome: A significant factor of tumor occurrence and development
Li, F., Gao, Y., Cheng, W., Su, L., & Yang, R. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216302 · Cited by 36
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“A recent study showed that human colon mucosal biofilms obtained from tumor hosts or healthy individuals are required for tumorigenesis in murine models of APCMin−/+ mice [59].”
BackgroundDoes the Gut Microbiota Modulate Host Physiology through Polymicrobial Biofilms?
Yang, J., Yang, Y., Ishii, M., Nagata, M., Aw, W., Obana, N., Tomita, M., Nomura, N., & Fukuda, S. (2020) · Microbes and Environments · doi:10.1264/jsme2.me20037 · Cited by 33
“The same group also discovered that biofilm communities on the colon epi‐ thelium prepared from CRC patients and even healthy indi‐ viduals were carcinogenic in murine CRC models (Tomkovich et al., 2019).”
BackgroundSelf-citationAnnavajhala, M. K., May, M. S., Compres, G., Freedberg, D. E., Graham, R., Stump, S., Que, J., Korem, T., Uhlemann, A., & Abrams, J. A. (2020) · Clinical and Translational Gastroenterology · doi:10.14309/ctg.0000000000000235 · Cited by 32
“In the colon, bio fi lms are present on proximal tumors and adjacent paired normal mucosa (15) and promote the development of colonic neoplasia in mice (16).”
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“Phase 1, single center ICI-refractory metastatic melanoma (10) FMT (two donors) by colonoscopy and oral capsules with anti-PD-1 ICI therapy One CR Two PR There were responses only with one of the two donors No serious adverse events were noted”
Self-citationThe oral-gut-circulatory axis: from homeostasis to colon cancer
Tortora, S. C., Agurto, M. I. G., & Martello, L. A. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1289452 · Cited by 34
Intestinal dysbiosis and colorectal cancer
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“[130] This is driven by immune cell infiltration, especially IL-17-producing cells, which are involved in fostering tumorigenesis.”
Crypt residing bacteria and proximal colonic carcinogenesis in a mouse model of Lynch syndrome
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“other researchers points to a mutagenic mucosal biofilm microbiota which can be transmitted from humans to tumor-susceptible mice.(4) Which microbes are residing in the mucus of tumor crypts and”
BackgroundTunçer, S., & Karaçam, S. (2020) · Archives of Microbiology · doi:10.1007/s00203-020-02005-8 · Cited by 29
“Besides, the recent reports emphasize that biofilm formation has a potential etiological role in the development of cancers attributable to chronic infection (Raskov et al. 2018; Li et al. 2019; Rizzato et al. 2019; Tomkovich et al. 2019).”
BackgroundThe Role of the Microbiome on the Pathogenesis and Treatment of Colorectal Cancer
Yu, I., Wu, R., Tokumaru, Y., Terracina, K. P., & Takabe, K. (2022) · Cancers · doi:10.3390/cancers14225685 · Cited by 30
Exploiting unique features of the gut-brain interface to combat gastrointestinal cancer
Schledwitz, A., Xie, G., & Raufman, J. (2021) · Journal of Clinical Investigation · doi:10.1172/jci143776 · Cited by 31
“Mucosal microbial biofilms from humans with CRC are carcinogenic in murine models (101), and some bacterial products (e.”
Sheikh, A. A., Taube, J. H., & Greathouse, K. L. (2021) · Carcinogenesis · doi:10.1093/carcin/bgab060 · Cited by 26
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Self-citationGut microbial biofilm composition and organisation holds the key to CRC
Hold, G. L., & Allen‐Vercoe, E. (2019) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-019-0148-4 · Cited by 25
Gut Microbiota and Colorectal Cancer Risk Factors
Feizi, H., Rezaee, M. A., Ghotaslou, R., Sadrkabir, M., Jadidi‐Niaragh, F., Gholizadeh, P., Taghizadeh, S., Ghanbarov, K., Yousefi, M., & Kafil, H. S. (2022) · Current Pharmaceutical Biotechnology · doi:10.2174/1389201023666221005103340 · Cited by 25
Fungi and tumors: The role of fungi in tumorigenesis (Review)
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“Interestingly, biofilm homogenates from patients with CRC can cause colon tumorigenesis in mice (62).”
Antibiotics, cancer risk and oncologic treatment efficacy: a practical review of the literature
Lopes, M. S. M., Machado, L. M., Silva, P. A. I. A., Uchiyama, A. A. T., Yen, C. T., Ricardo, E. D., Mutão, T. S., Pimento, J. R., Shimba, D. S., Hanriot, R. D. M., et al. (2020) · ecancermedicalscience · doi:10.3332/ecancer.2020.1106 · Cited by 25
A tale of two bacteria – Bacteroides fragilis, Escherichia coli, and colorectal cancer
Lichtenstern, C. R., & Lamichhane-Khadka, R. (2023) · Frontiers in Bacteriology · doi:10.3389/fbrio.2023.1229077 · Cited by 23
Cancer microbiota: a focus on tumor-resident bacteria
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“Moreover, some of the bacterial species form bio fi lm, which consists of complex microbial communities enclosed in self-produced polymeric matrix, facilitating their protection to the immune system (Chessa et al, 2016; Drusano et al, 2011; Tomkovich et al, 2019).”
Biofilm Formation and Virulence of Shigella flexneri Are Modulated by pH of Gastrointestinal Tract
Chiang, I.-L., Wang, Y., Fujii, S., Muegge, B. D., Lu, Q., Tarr, P. I., & Stappenbeck, T. S. (2021) · Infection and Immunity · doi:10.1128/iai.00387-21 · Cited by 22
“Our work may have implications beyond acute Shigella infections, as gut biofilms have been associated with colorectal cancer and inflammatory bowel disease, and may further the investigation of biofilms related to disorders of the gastrointestinal tract (32, 33).”
Background
Metadata
- Authors
- Tomkovich, S., Dejea, C. M., Winglee, K., Drewes, J. L., Chung, L., Housseau, F., Pope, J. L., Gauthier, J., Sun, X., Mühlbauer, M., Liu, X., Fathi, P., Anders, R. A., Besharati, S., Perez-Chanona, E., Yang, Y., Ding, H., Wu, X., Wu, S., White, J. R., Gharaibeh, R. Z., Fodor, A. A., Wang, H., Pardoll, D. M., Jobin, C., & Sears, C. L.
- Affiliations
- University of Florida (US)
- Johns Hopkins University (US)
- University of North Carolina at Charlotte (US)
- Resphera Biosciences (US)
- Corresponding author
- Jobin, Christian
- Sears, Cynthia L.
- ORCID
- Tomkovich, Sarah
- Dejea, Christine M.
- Winglee, Kathryn
- Drewes, Julia L.
- Chung, Liam
- Housseau, Franck
- Sun, Xiaolun
- Mühlbauer, Marcus
- Liu, Xiuli
- Anders, Robert A.
- Besharati, Sepideh
- Yang, Ye
- Ding, Hua
- Wu, Xinqun
- Wu, Shaoguang
- White, James R.
- Gharaibeh, Raad Z.
- Fodor, Anthony A.
- Wang, Hao
- Pardoll, Drew M.
- Jobin, Christian
- Sears, Cynthia L.
- Venue
- Journal of Clinical Investigation
- Published
- 2019-03-11
- Volume
- 129
- Issue
- 4
- Pages
- 1699-1712
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6436866
- OpenAlex
- W2921953499
- Cited by
- 209
- References
- 49
- Citations by year
- 2026: 15 · 2025: 20 · 2024: 29 · 2023: 33 · 2022: 24 · 2021: 45 · 2020: 31 · 2019: 11
- FWCI
- 9.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH (R01DK073338, R01DK47700, R01 CA151393, R01CA196845, P50 CA62924, P30 CA006973, P30 DK089502, K99 CA230192, S10OD016374)
- Bloomberg Philanthropies (Microbiome Project)
- Johns Hopkins Discovery Award (Internal award)
- Commonwealth Foundation (Johns Hopkins)
- Cancer Research Institute/Fight Colorectal Cancer coalition (CRC discovery award)
- University of Florida Health Cancer Center Funds (internal award)
- University of Florida Department of Medicine Gatorade Fund (internal award)
- Crohn’s and Colitis Foundation (CCFA Ref. #409472)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bacterial biofilms and quorum sensing
- Life Sciences › Immunology and Microbiology › Microbiology › Escherichia coli research studies
- Keywords
- colorectal cancer, carcinogenesis, gut microbiota, ApcMin/+ mice, germ-free mice, colonic inflammation, tumor formation, microbial communities, 16S rRNA gene sequencing, RNA-seq
- MeSH terms
- Gastrointestinal Microbiome, Animals, Colon, Colonic Neoplasms, Humans, Neoplasms, Experimental, Mice, Knockout, Biofilms, Mice, Carcinogenesis
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